PROJECT SUMMARY Over the last few years, human genetics studies in psychiatric genetics have been successful in identifying genes associated with various behavioral disorders, such as schizophrenia, bipolar disorder, autism, and more recently, drug abuse and addiction. The next phase, developing approaches to understand the specific variants associated with risk and their functional impact, will be critical in order to translate these successes toward improved treatment. A non-synonymous SNP (rs1260326; P466L) in the human GCKR (coding for the glucokinase regulatory protein) gene is emerging as a robust and replicable association with alcohol consumption. However, statistical associations from human genetic studies provide little information about how or why a SNP may be important to a phenotype. Human statistical genetics studies inherently lack experimenter control and the phenotypes are broad and full of variability not easily captured by statistical associations. It is therefore important to translate these human genetic findings to model systems that provide the experimental control and refined phenotypes necessary for a functional understanding of a SNP's influence on disease. We therefore propose to develop a knock-in mouse containing the P466L risk allele (rs1260326) and characterize it for alcohol consummatory behavior (24-hr two-bottle choice alcohol drinking and Drinking in the Dark) and alcohol metabolism. The aims proposed herein will advance the field by creating a novel mouse model based on a human risk variant and then carefully characterizing its alcohol behaviors. Further, the rs1260326 SNP has been associated with over 25 other human phenotypes (e.g. Type II Diabetes, impairment of insulin secretion, cardiovascular diseases) and therefore will have utility for a number of researchers across a wide range of scientific disciplines. Collectively, Dr. Powers and Dr. Ehringer have had many years of experience using human and mouse genetics approaches to study behavioral phenotypes associated with alcohol-use disorders and are therefore ideally suited to apply their complementary areas of expertise to address these important questions.